CN111171077A - 喜树碱衍生物及其制备方法和应用 - Google Patents
喜树碱衍生物及其制备方法和应用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
一系列喜树碱衍生物，以及该些喜树碱衍生物的制备方法和该些喜树碱衍生物在核酸适配体修饰中的应用。所述喜树碱衍生物具有式I所示的结构。在本申请中，在喜树碱衍生物，尤其是10‑羟基喜树碱衍生物的10位上进行化学修饰，合成了一系列喜树碱衍生物。合成的喜树碱衍生物可以引入到核酸适体中，以有效的提高其溶解性和选择性，并降低毒副作用，为喜树碱类药物应用于临床提供了新的途径。
Description
技术领域
本发明涉及医药领域，特别涉及一系列喜树碱衍生物，以及该喜树碱衍生物的制备方法，以及该喜树碱衍生物在医药中的应用，尤其是在核酸适体修饰中的应用。
背景技术
世界卫生组织(WHO)发布的数据显示，我国已经成为全球新增癌症病例最多的国家，其中肝、胃、肺和食道等四种恶性肿瘤中，中国新增病例和死亡人数均居世界首位。作为治疗重要方法之一，化疗存在毒副作用显著的缺点，在杀死癌细胞的同时，药物分子也破坏正常细胞。癌症治疗的另一个普遍存在的问题是治疗过程中产生肿瘤耐药，这是困扰治疗效果的一大难题。
针对药物的毒副作用开展地长期研究发现，将具有靶向性的配体分子与具有良好活性的药物分子连接，相应的偶联物具有毒副作用低、疗效好的优点。靶向治疗在临床应用中发挥越来越重要的作用。核酸适体是一类能特异性与靶标结合的单链DNA或RNA，又被称为化学抗体。应用该配体分子作为载体的核酸适体-药物偶联物(Aptamer-DrugConjugate，ApDC)研究处于高速发展中。与抗体相比较，核酸适体具有以下几个特点，可能是更具潜力的药物载体：1)通过化学方法合成制备，更易于进行结构修饰与改性，实现更多药物形式的可控、高效构建；2)易于大规模制备、批次稳定、生产成本更低；3)没有明显的免疫原性，在生物体内安全性更高；4)体积小，具有更好的组织穿透性。
早期核酸适体与药物偶联的方式与ADC技术类似，即首先合成得到核酸适体，再通过各种方法将核酸适体与药物进行偶联，但这种通过手动方式将核酸适体与药物进行反应制备而成，没有利用核酸适体的化学合成这一特点。而将小分子药物通过有机合成反应转化为固相合成模块，应用该模块即可通过固相合成仪自动化、高效合成ApDC。这一方法可有效解决ApDC载药效率低以及制备复杂的问题。
在ApDC药物中，核酸适体是起着靶向作用的配体分子，所选用的药物更偏重于其广谱抑制活性。
从喜树里提取的天然产物喜树碱是优异的DNA拓扑异构酶I抑制剂，但受限于其溶解性与毒副作用，未能进入临床应用。
因此，有必要提出一种新的喜树碱衍生物，使其具有良好溶解性、高选择性及低毒副作用，进而使得喜树碱能够进入临床应用，为喜树碱类药物应用于临床提供了创新性的方法。
发明内容
本发明的目的在于提供一系列喜树碱衍生物，尤其是10-羟基喜树碱衍生物的10位上进行化学修饰而合成的一系列喜树碱衍生物。合成的喜树碱衍生物可以自动化、高效地引入到核酸适体中，以有效地提高其溶解性和选择性，并降低毒副作用，为喜树碱类药物应用于临床提供了新的途径。
为了达到上述目的，根据本发明的一方面，提供一种喜树碱衍生物，具有式I所示的结构：
其中，R1为H、取代或未取代的具有1-4个碳原子的直链或支链烷基、-C(O)Ra1、-CNRb1Rc1或-NO2；
R2为H、取代或未取代的具有1-4个碳原子的直链或支链烷基、-C(O)Ra1、-CNRb1Rc1或-NO2；
R3为H或羟基保护基；
X为O或N；
L为取代或未取代的具有1-20个碳原子的直链或支链杂烷基；
W为H或-COWa1；
Ra1、Rb1、Rc1独立地为具有1-4个碳原子的直链或支链烷基；
Wa1为保护基团。
在一些实施例中，所述喜树碱衍生物具有式I-a所示的结构：
其中，L1为取代或未取代的具有1-6个碳原子的直链或支链烷基；L2为取代或未取代的具有1-14个碳原子的直链或支链杂烷基。
在一些实施例中，所述喜树碱衍生物尤其具有式I-a-1或式I-a-2所示的结构：
其中，L1为取代或未取代的具有1-6个碳原子的直链或支链烷基；L2为取代或未取代的具有1-14个碳原子的直链或支链杂烷基。
在一些实施例中，所述具有1-20个碳原子的直链或支链杂烷基的杂原子为O或S。
在一些实施例中，所述保护基团为4,4’-二甲氧基三苯甲基(DMTr)。
在一些实施例中，所述羟基保护基为-TMS，-TBS，-TBDPS，-MOM，或-Ac。
在一些实施例中，当R1、R2或L被取代时，取代基独立地选自具有1-4个碳原子的烷基或苯基。
根据本申请的另一方面，提供上述喜树碱衍生物的制备方法，是以羟基喜树碱与烯基溴化合物反应完全后，加入羟基保护试剂并以4-二甲氨基吡啶为催化剂反应至完全，以获得中间产物1；在保护气体下，以偶氮二异丁腈为引发剂，使中间产物1与硫醇类化合物或硫代甘油反应至完全以获得中间产物2或中间产物3；以4-二甲氨基吡啶为催化剂，使中间产物3与DMTrCl室温反应至完全以获得中间产物4；在N,N-二异丙基乙胺的催化下，分别使中间产物2或4与2-氰乙基-N,N-二异丙基氯代亚磷酰胺室温反应完全，以获得目标产物1或2；其中，目标产物1具有式I-a-1所示的结构，目标产物2具有式I-a-2所示的结构。
在一些实施例中，所述羟基保护试剂为乙酸酐、MOMCl、TBSCl、TBDPSCl或TMSCl。
根据本申请的另一方面，还提供上述喜树碱衍生物在核酸适体修饰中的应用，尤其是在核酸适体sgc8的修饰中的应用。
在一些实施例中，以固相合成仪将所述喜树碱衍生物引入核酸适体。
本领域技术人员可以理解的是，在本申请中，所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕、氘(D，又称为重氢)、氚(又称为超重氢)，氧的同位素包括160、170和180，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N。
在本申请中，“烷基”是指直链和支链的饱和脂肪族烃基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,2-二甲基己基、2,3-二甲基己基、2,4-二甲基己基、2,5二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基和正癸基。
在本申请中，“杂烷基”是指包含至少一个选自O或S的杂原子的烷基。
在本申请中，上述烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被任意合适的取代基取代。
在本申请中，在喜树碱衍生物，尤其是10-羟基喜树碱衍生物的10位上进行化学修饰，以合成一系列喜树碱衍生物。合成的喜树碱衍生物可以引入到核酸适体中，以有效的提高其溶解性和选择性，并降低毒副作用，为喜树碱类药物应用于临床提供了新的途径。
具体实施方式
以下，结合具体实施方式，对本发明的技术进行详细描述。应当知道的是，以下具体实施方式仅用于帮助本领域技术人员理解本发明，而非对本发明的限制。
实施例1.喜树碱衍生物
在本实施例中提供一种喜树碱衍生物尤其具有式I-a-1或式I-a-2所示的结构：
其中，L1为取代或未取代的具有1-6个碳原子的直链或支链烷基；L2为取代或未取代的具有1-14个碳原子的直链或支链杂烷基。优选地，所述具有1-14个碳原子的直链或支链杂烷基的杂原子为O或S，尤其优选地，所述具有1-14个碳原子的直链或支链杂烷基的杂原子为O。即，所述具有1-14个碳原子的直链或支链烷基中的碳原子的一个或多个被O替换。
在本实施例中，还提供上述喜树碱衍生物的制备方法，所述制备方法是以以羟基喜树碱与烯基溴化合物反应完全后，加入羟基保护试剂并以4-二甲氨基吡啶为催化剂反应至完全，以获得中间产物1；在保护气体下，以偶氮二异丁腈为引发剂，使中间产物1与硫醇类化合物反应至完全以获得中间产物2，而中间产物1与硫代甘油反应至完全以获得中间产物3；以4-二甲氨基吡啶为催化剂，使中间产物3与DMTrCl室温反应至完全以获得中间产物4；在N,N-二异丙基乙胺的催化下，分别使中间产物2或4与2-氰乙基-N,N-二异丙基氯代亚磷酰胺室温反应完全，以获得具有式I-a-1所示结构的目标产物1或具有式I-a-2所示结构的目标产物2。
本领域技术人员可以理解的是，所述制备方法的每一步骤均可以包含洗涤纯化步骤，例如用去离子水多次洗涤析出、柱层析分离纯化等步骤。
在本实施例中，所述羟基保护试剂例如但不限于乙酸酐、MOMCl、TBSCl、TBDPSCl或TMSCl。
在本实施例中，提供上述式I-a-1及式I-a-2所示结构的喜树碱衍生物的具体合成步骤如下。
具体步骤包括以下步骤：
步骤1：取50mL的圆底烧瓶，向羟基喜树碱(1mmol)的DMF溶液中，依次加入无水碳酸钾(3.0eq)，烯基溴类化合物(3.0eq),50℃加热搅拌3小时。经TLC检测确认原料消耗完全后，将反应混合液倒入水中，用稀盐酸调至酸性，过滤，用去离子水多次洗涤析出沉淀固体，抽干，得到化合物1。
步骤2：取50mL的圆底烧瓶，向化合物1(1mmol)的DCM溶液中，依次加DMAP(0.05eq)，吡啶(10ml)，加入羟基保护试剂(例如：乙酸酐、MOMCl、TBSCl、TBDPSCl或TMSCl，2.0eq),室温搅拌过夜。经TLC检测确认原料消耗完全后，将反应混合液倒入水中，分液，收集有机相，水相有乙酸乙酯萃取(三次)，合并有机相，用无水硫酸钠干燥，减压旋蒸，旋干有机相，柱层析分离纯化(PE/EtOAc),得到化合物2。
步骤3：取50mL的两口圆底烧瓶，在氮气保护下，向化合物2(1mmol)的DMF溶液中，依次加入AIBN(0.5eq)，硫醇类化合物(5.0-10.0eq)，80℃加热搅拌4小时，经TLC检测确认原料消耗完全后，将反应混合液倒入水中，用乙酸乙酯萃取(三次)，合并有机相，用无水硫酸钠干燥，减压旋蒸，旋干有机相，柱层析分离纯化(DCM/MeOH),当使用的硫醇为仅含有一个醇羟基时得到化合物3；当使用的硫醇为硫代甘油时得到化合物5。
步骤4：取50mL的两口圆底烧瓶，在氮气保护下，向化合物3(1mmol)的干燥吡啶溶液中，依次加入DMAP(0.05eq)，DMTrCl(1.2eq)，室温搅拌过夜，经TLC检测确认原料消耗完全后，反应液减压旋蒸，旋干吡啶溶剂，柱层析分离纯化(DCM/MeOH)，得到化合物6。
步骤5：取50mL的两口圆底烧瓶，在氮气保护下，向化合物3或6(1mmol)的干燥DCM溶液中，加入DIPEA(2.0eq)，然后在0℃条件下，缓慢滴加2-氰乙基-N,N-二异丙基氯代亚磷酰胺(1.2eq)，室温反应2小时后，经TLC检测确认原料消耗完全后，将反应液倒入水中，依次使用饱和NaHCO3溶液、饱和NaCl溶液洗涤有机相，用无水硫酸钠干燥有机相，减压旋蒸，旋干，柱层析分离纯化(PE/EtOAc),得到化合物，得到目标产物4或7。
实施例2.具体的喜树碱衍生物
在本实施例中，具体合成了一系列喜树碱衍生物。申请人还对该一系列喜树碱衍生物进行了核磁验证，具体验证数据如下记载。
上述化合物的核磁验证数据如下记载
1H NMR(500MHz,CDCl3)δH 7.71(d,J＝15.0Hz,1H),7.44(d,J＝2.9Hz,1H),7.27(dd,J＝14.9,3.0Hz,1H),6.74(s,1H),5.80(d,J＝17.0Hz,1H),5.52(d,J＝17.0Hz,1H)，4.22(s,2H),4.05(t,J＝14.9Hz,2H),3.94-3.81(m,2H),3.51(q,J＝13.2Hz,2H),3.31(t,J＝14.9Hz,2H),2.95-2.84(m,2H),2.70(t,J＝6.5Hz,2H),2.60–2.51(m,4H),2.36–2.20(m,4H),1.23(dd,J＝6.8,2.3Hz,12H),1.19(t,J＝13.2Hz,3H),0.91(t,J＝13.6Hz,3H)；13CNMR(125MHz,CDCl3)δC 172.1,169.1,158.2,157.8,156.3,145.4,143.7,142.0,132.8,132.3,132.0,123.2,119.6,118.6,118.4,113.2,103.7,97.7,80.1,68.8,63.4,63.1,62.3,59.1,59.0,51.3,44.6,44.5,32.8,32.6,31.4,29.8,29.6,27.3,22.9,22.8,21.8,14.3,7.9；31P NMR(202MHz,CDCl3)δP147.7；HRMS m/z(ESI)calcd for C36H47N4O7PS+[M+H]+:710.2903,found:710.2900.
1H NMR(500MHz,CDCl3)δH7.67(d,J＝15.0Hz,1H),7.40(d,J＝2.9Hz,1H),7.23(dd,J＝14.9,3.0Hz,1H),6.93(s,1H),5.79(d,J＝17.0Hz,1H),5.52(d,J＝17.0Hz,1H),4.95(s,2H),4.09(t,J＝14.9Hz,2H),3.91-3.80(m,2H),3.47(q,J＝13.2Hz,2H),3.31(t,J＝14.9Hz,2H),2.97-2.85(m,2H),2.70(t,J＝6.5Hz,2H),2.59–2.46(m,4H),2.26–2.00(m,7H),1.20(dd,J＝6.8,2.3Hz,12H),1.17(t,J＝13.2Hz,3H),0.89(t,J＝13.6Hz,3H)；13CNMR(125MHz,CDCl3)δC173.1,169.5,159.2,157.2,156.6,146.4,144.6,141.0,132.6,132.1,132.0,125.2,119.1,118.3,117.4,115.2,104.7,97.5,81.1,68.6,63.5,63.0,62.0,59.5,59.0,51.3,44.6,44.3,33.8,31.6,30.2,29.7,29.5,26.3,22.5,22.3,14.3,7.9；31P NMR(202MHz,CDCl3)δP147.7；HRMS m/z(ESI)calcdforC38H50N4O8PS+[M+H]+:753.3081,found:753.3076.
1H NMR(500MHz,CDCl3)δH8.13(d,J＝9.2Hz,1H),7.49(dd,J＝9.2,2.6Hz,1H),7.36(d,J＝2.4Hz,1H),7.16(s,1H),5.69(d,J＝17.0Hz,1H),5.42(d,J＝17.0Hz,1H),5.24(d,J＝2.6Hz,2H),4.28(t,J＝6.0Hz,2H),4.25-4.12(m,1H),3.94-3.81(m,3H),3.78-3.70(m,3H),3.68-3.49(m,5H),2.86(t,J＝7.0Hz,2H),2.79(t,J＝5.0Hz,2H),2.66(t,J＝6.5Hz,2H),2.35-2.25(m,1H),2.22(s,3H),2.21-2.12(m,3H),1.42(t,J＝7.7Hz,3H),1.20(dd,J＝6.8,2.3Hz,12H),0.99(t,J＝7.5Hz,3H)；13C NMR(125MHz,CDCl3)δC173.1,169.1,158.4,158.2,153.6,145.2,143.9,136.9,132.2,132.0,123.6,119.7,118.6,118.4,117.5,103.7,95.3,77.7,71.2,71.0,68.8,67.7,63.3,60.8,60.7,59.1,59.0,50.3,44.6,44.5,31.7,31.4,29.8,29.2,26.3,22.9,22.8,21.8,14.3,7.9；31P NMR(202MHz,CDCl3)δP148.7；HRMS m/z(ESI)calcdforC40H54N4O9PS+[M+H]+:797.3344,found:797.3342.
1H NMR(500MHz,CDCl3)δ7.71(d,J＝15.0Hz,1H),7.44(d,J＝3.1Hz,1H),7.27(dd,J＝14.9,3.0Hz,1H),6.96(s,1H),5.78(s,1H),5.66(s,1H),4.98(s,2H),4.11(t,J＝15.0Hz,2H),3.86(t,J＝8.0,1H),3.79–3.65(m,4H),3.59–3.42(m,8H),3.50(t,J＝7.1,2H),2.83(m,2H),2.61–2.45(m,4H),2.27–2.00(m,7H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ173.1,169.1,158.4,153.6,152.4,145.2,143.9,143.1,136.9,132.1,132.0,123.6,119.7,117.5,103.7,95.3,77.7,71.2,71.1,69.9,68.8,67.6,63.3,63.0,62.9,60.8,60.7,50.3,46.4,46.3,44.6,44.5,31.7,31.4,29.8,29.3,26.2,22.9,22.8,21.8,14.3,7.9；31P NMR(202MHz,CDCl3)δP146.7；HRMS m/z(ESI)calcd for C42H58N4O10PS+[M+H]+:841.3606,found:841.3601.
1H NMR(500MHz,CDCl3)δH7.68(d,J＝15.0Hz,1H),7.41(d,J＝3.1Hz,1H),7.24(dd,J＝14.9,3.0Hz,1H),6.94(s,1H),5.76(s,1H),5.64(s,1H),4.96(s,2H),4.09(t,J＝14.9Hz,2H),3.90(t,J＝8.0,2H),3.78–3.61(m,4H),3.56–3.42(m,12H),2.85-2.78(m,2H),2.60(t,J＝8.0,2H),2.51(m,4H),2.26–2.00(m,7H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ173.1,168.1,158.5,158.4,153.6,145.2,143.9,143.0,136.8,132.0,129.9,123.5,119.6,118.6,118.5,117.5,103.7,95.2,77.7,71.1,71.0,69.9,68.8,67.6,63.2,60.7,60.6,59.0,49.9,50.2,44.5,44.4,31.7,31.4,29.829.226.1,23.0,22.9,21.8,14.3,7.7；31P NMR(202MHz,CDCl3)δP 148.5；HRMSm/z(ESI)calcd for C44H62N4O11PS+[M+H]+:885.3868,found:885.3860.
1H NMR(500MHz,CDCl3)δH7.71(d,J＝15.0Hz,1H),7.44(d,J＝3.1Hz,1H),7.27(dd,J＝15.0,3.1Hz,1H),6.96(s,1H),5.78(s,1H),5.66(s,1H),4.99(s,2H),4.11(t,J＝14.9Hz,2H),3.90(t,J＝8.0,2H),3.77–3.65(m,4H),3.58–3.41(m,16H),2.84-2.74(m,2H),2.60(t,J＝8.0,2H),2.52(m,4H),2.39(q,J＝13.5Hz,1H),2.21–2.07(m,6H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ173.2,169.1,158.3,158.2,153.6,145.2,143.9,143.1,136.9,132.1,132.0123.6,119.7,118.7,118.6,117.5,103.7,95.2,77.7,71.2,71.1,69.9,68.8,67.6,64.2,61.8,61.7,58.1,58.0,50.3,45.6,45.5,31.7,31.4,28.8,28.2,25.1,21.9,21.8,21.7,14.3,7.8；31PNMR(202MHz,CDCl3)δP 147.5；HRMS m/z(ESI)calcd for C46H66N4O12PS+[M+H]+:929.4310,found:929.4315.
1H NMR(500MHz,CDCl3)δ7.71(d,J＝15.0Hz,1H),7.44(d,J＝2.9Hz,1H),7.27(dd,J＝15.0,2.9Hz,1H),6.96(s,1H),5.77(s,1H),5.66(s,1H),4.97(s,2H),4.11(t,J＝14.9Hz,2H),3.90(t,J＝8.0,2H),3.78–3.63(m,4H),3.60–3.41(m,20H),2.82-2.73(m,2H),2.60(t,J＝8.0,2H),2.61–2.42(m,4H),2.32–1.95(m,7H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ171.1,168.1,158.4,158.2,153.8,145.2,143.8,143.0,136.9,132.1,132.0,123.6,119.7,118.5,118.4,117.2,103.7,95.7,77.7,71.2,69.8,68.8,67.7,63.3,60.8,60.7,59.1,59.0,50.3,44.6,44.5,31.7,31.4,29.8,29.3,26.3,22.9,22.8,21.8,14.3,8.0；31P NMR(202MHz,CDCl3)δP 149.5；HRMS m/z(ESI)calcd for C48H70N4O13PS+[M+H]+:973.4392,found:973.4399.
1H NMR(500MHz,CDCl3)δ7.71(d,J＝7.5Hz,1H),7.44(d,J＝1.6Hz,1H),7.27(dd,J＝7.4,1.5Hz,1H),6.96(s,1H),5.78(s,1H),5.66(s,1H),4.99(d,J＝1.2Hz,2H),4.11(t,J＝7.5Hz,2H),3.90(t,J＝8.0,2H),3.71(dt,J＝12.8,7.5Hz,4H),3.58–3.45(m,24H),2.80-2.71(m,2H),2.60(t,J＝8.0,2H),2.53(dt,J＝14.7,7.8Hz,4H),2.39(q,J＝6.8Hz,1H),2.19–2.11(m,3H),2.09(s,3H),1.18(t,J＝6.6Hz,3H),1.06(d,J＝6.8,12H),0.89(t,J＝6.8Hz,3H)；13C NMR(125MHz,CDCl3)δ174.1,170.0,157.4,157.3,153.6,144.2,143.9,143.1,135.9,131.0,131.1,123.6,118.7,117.8,117.7,117.5,102.7,96.3,78.7,71.3,71.2,70.0,68.2,67.6,63.28,61.8,61.7,58.1,58.0,51.2,43.5,43.4,32.7,30.4,29.8,29.2,26.1,23.0,22.9,21.7,14.2,7.6；31P NMR(202MHz,CDCl3)δP 148.1；HRMS m/z(ESI)calcdforC50H74N4O14PS+[M+H]+:1017.4654,found:1017.4650.
1H NMR(500MHz,CDCl3)δ7.71(d,J＝15.0Hz,1H),7.44(d,J＝2.9Hz,1H),7.27(dd,J＝15.0,2.9Hz,1H),6.96(s,1H),5.78(s,1H),5.66(s,1H),4.98(s,2H),4.11(t,J＝15.0Hz,2H),3.90(t,J＝8.0,2H),3.79–3.65(m,4H),3.60–3.42(m,28H),2.85-2.77(m,2H),2.60–2.45(m,6H),2.25–2.01(m,7H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ172.1,169.1,158.4,158.3,153.6,145.3,143.9,143.0,136.9,132.3,132.2,123.6,119.7,118.6,118.5,117.6,103.7,95.7,77.7,71.2,71.0,69.9,68.8,67.6,63.3,60.9,60.8,50.3,44.5,44.4,31.6,31.4,29.8,29.3,26.3,23.0,22.9,21.8,14.3,7.9；31P NMR(202MHz,CDCl3)δP 148.1；HRMS m/z(ESI)calcd for C52H78N4O15PS+[M+H]+:1061.4917,found:1061.4919.
1H NMR(500MHz,CDCl3)δ7.71(d,J＝15.0Hz,1H),7.44(d,J＝3.1Hz,1H),7.27(dd,J＝14.9,3.0Hz,1H),6.96(s,1H),5.79(s,1H),5.65(s,1H),4.98(s,2H),4.11(t,J＝13.9Hz,2H),3.90(t,J＝8.0,2H),3.63–3.38(m,4H),2.83-2.76(m,2H),2.61–2.45(m,6H),2.27–2.02(m,7H),1.92(m,2H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ173.1,167.1,156.4,156.3,153.6,146.2,143.9,143.0,136.9,132.3,132.2,123.6,118.6,118.3,118.2,117.5,103.7,95.3,77.6,68.8,63.3,62.3,62.2,59.1,59.0,50.3,44.6,44.5,31.9,31.8,31.4,29.8,29.3,26.3,22.9,22.8,21.8,14.3,7.6；31P NMR(202MHz,CDCl3)δP 147.1；HRMSm/z(ESI)calcd forC39H52N4O8PS+[M+H]+:767.3238,found:767.3235.
1H NMR(500MHz,CDCl3)δ7.71(d,J＝15.0Hz,1H),7.44(d,J＝2.9Hz,1H),7.27(dd,J＝15.0,2.9Hz,1H),6.96(s,1H),5.79(s,1H),5.65(s,1H),4.97(s,2H),4.11(t,J＝14.9Hz,2H),3.90(t,J＝8.0,2H),3.62(t,J＝14.3Hz,2H),3.49(q,J＝13.2Hz,2H),2.83-2.77(m,2H),2.60–2.43(m,6H),2.27–2.01(m,7H),1.66–1.35(m,8H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ173.2,169.1,158.4,158.3,153.6,145.2,143.9,143.1,136.9,132.1,132.0,123.6,119.7,118.7,118.6,117.5,103.7,95.3,77.5,68.8,63.3,63.2,63.1,59.1,59.0,50.3,44.6,44.5,32.8,31.4,30.5,30.4,29.8,29.5,29.3,29.0,26.6,26.1,22.9,22.8,21.8,15.3,8.1；31PNMR(202MHz,CDCl3)δP 147.1；HRMS m/z(ESI)calcd for C42H58N4O8PS+[M+H]+:809.3707,found:809.3705.
1H NMR(500MHz,CDCl3)δ7.71(d,J＝15.0Hz,1H),7.44(d,J＝3.1Hz,1H),7.27(dd,J＝14.9,3.0Hz,1H),6.96(s,1H),5.78(s,1H),5.66(s,1H),4.99(s,2H),4.11(t,J＝14.9Hz,2H),3.90(t,J＝8.0,2H),3.62(t,J＝14.8Hz,2H),3.49(q,J＝13.2Hz,2H),2.83-2.74(m,2H),2.60–2.45(m,6H),2.39(q,J＝13.5Hz,1H),2.22–2.04(m,6H),1.66–1.25(m,19H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ171.1,168.1,159.2,159.1,153.7,145.2,143.9,143.0,136.9,132.3,132.2,123.6,119.7,118.6,118.5,117.2,103.7,95.4,77.1,68.8,63.2,63.1,63.0,59.1,59.0,50.3,44.7,44.6,32.8,31.4,30.6,30.5,29.8,29.5,29.3,29.0,26.6,26.2,22.8,22.7,21.8,15.3,7.7；31P NMR(202MHz,CDCl3)δP147.5；HRMS m/z(ESI)calcd forC48H70N4O8PS+[M+H]+:893.4646,found:893.4641.
1H NMR(500MHz,CDCl3)δ7.71(d,J＝15.0Hz,1H),7.44(d,J＝3.1Hz,1H),7.27(dd,J＝14.9,3.0Hz,1H),6.96(s,1H),5.79(s,1H),5.65(s,1H),4.98(s,2H),4.00(t,J＝14.6Hz,2H),3.96-3.88(m,4H),3.49(q,J＝13.2Hz,2H),2.85-2.80(m,3H),2.70(t,J＝14.6Hz,2H),2.60(t,J＝8.0,2H),2.21(q,J＝13.6Hz,1H),2.13–2.00(m,6H),1.29(d,J＝12.8Hz,3H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H)；13CNMR(125MHz,CDCl3)δ171.1,167.1,156.4,156.3,153.6,145.2,143.9,143.1,136.9,132.1,132.0,123.6,120.0,119.6,119.5,117.5,103.7,95.3,78.2,69.9,63.7,63.6,63.1,59.2,59.1,50.3,44.9,44.8,39.2,37.1,31.5,31.4,29.3,26.2,22.6,22.5,21.6,21.0,13.3,8.0；31P NMR(202MHz,CDCl3)δP 147.3；HRMS m/z(ESI)calcd for C39H52N4O8PS+[M+H]+:767.3238,found:767.3236.
1H NMR(500MHz,CDCl3)δ7.71(d,J＝14.9Hz,1H),7.44(d,J＝3.1Hz,1H),7.39–7.12(m,6H),7.02(s,1H),5.74(s,1H),5.66(s,1H),4.93(s,2H),4.01–3.78(m,7H),3.49(q,J＝13.2Hz,2H),2.88–2.54(m,7H),2.42(q,J＝15.1Hz,2H),2.09(s,3H),2.03(dd,J＝27.2,13.6Hz,1H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ174.1,169.2,159.4,159.3,153.7,145.2,144.0,143.9,143.1,135.9,132.0,129.9,128.8,127.8,126.2,123.6,119.7,118.7,118.6,116.5,105.7,96.3,79.7,68.4,63.8,63.7,63.5,59.5,59.1,53.3,50.3,44.7,44.6,34.7,31.4,31.2,29.3,28.2,23.0,22.9,21.8,16.3,7.9；31P NMR(202MHz,CDCl3)δP 148.3；HRMS m/z(ESI)calcdfor C44H54N4O8PS+[M+H]+:829.3394,found:829.3390.
1H NMR(500MHz,CDCl3)δ7.71(d,J＝15.0Hz,1H),7.44(d,J＝3.1Hz,1H),7.27(dd,J＝14.9,3.0Hz,1H),7.03(s,1H),5.76(s,1H),5.67(s,1H),4.93(s,2H),4.11(t,J＝14.0Hz,2H),3.90(t,J＝8.0,2H),3.49(q,J＝13.2Hz,2H),3.33(t,J＝15.1Hz,2H),2.83-2.73(m,3H),,2.62-2.54(m,4H),2.14–1.97(m,6H),1.33(s,6H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ173.1,169.1,158.4,158.3,153.6,145.2,143.9,143.1,136.9,132.8,132.0,123.6,119.7,118.8,118.6,117.5,103.7,95.3,77.7,70.8,64.5,64.0,63.3,59.3,59.1,50.3,45.0,44.6,43.4,42.2,23.0,29.9,29.3,26.2,23.0,22.9,21.8,14.3,7.9；31P NMR(202MHz,CDCl3)δP148.3；HRMS m/z(ESI)calcd for C40H54N4O8PS+[M+H]+:781.3394,found:781.3391.
1H NMR(500MHz,CDCl3)δ7.69(d,J＝14.9Hz,1H),7.42(d,J＝3.1Hz,1H),7.25(dd,J＝14.9,3.0Hz,1H),6.96(s,1H),5.78(s,1H),5.64(s,1H),4.97(s,2H),4.10–3.97(m,1H),3.90(t,J＝8.0,2H),3.75(dd,J＝24.7,12.3Hz,1H),3.48(q,J＝13.2Hz,2H),3.32(t,J＝13.3Hz,2H),2.84-2.78(m,2H),2.70(t,J＝13.4Hz,2H),2.60-2.50(m,4H),2.36–2.20(m,2H),2.17–2.02(m,4H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.95(d,J＝12.7Hz,3H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ172.7,169.7,158.5,157.2,153.1,145.8,143.6,143.0,136.7,131.7,131.6,123.6,119.2,118.0,117.9,117.2,104.7,97.3,79.7,72.0,63.6,63.5,63.4,59.1,58.7,50.3,44.6,44.3,37.8,33.0,32.8,32.3,29.3,26.2,22.9,22.7,20.8,16.7,14.6,7.6；31P NMR(202MHz,CDCl3)δP 147.6；HRMSm/z(ESI)calcd for C39H52N4O8PS+[M+H]+:767.3238,found:767.3236.
1H NMR(500MHz,CDCl3)δ7.71(d,J＝14.9Hz,1H),7.44(d,J＝2.9Hz,1H),7.27(dd,J＝15.0,2.9Hz,1H),6.96(s,1H),5.79(s,1H),5.65(s,1H),4.98(s,2H),4.11(t,J＝14.9Hz,2H),3.90(t,J＝8.0,2H),3.80(t,J＝14.8Hz,2H),3.49(q,J＝13.1Hz,2H),2.84–2.50(m,7H),2.28–1.99(m,7H),1.93–1.77(m,2H),1.67–1.61(m,2H),1.48–1.30(m,2H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.89(t,J＝13.4Hz,6H)；13C NMR(125MHz,CDCl3)δ171.7,167.1,158.6,158.2,153.7,145.0,143.2,143.0,136.9,132.7,132.3,123.6,119.8,118.6,118.3,117.2,103.7,95.7,78.2,68.7,63.3,61.4,61.0,59.6,59.1,50.3,45.6,44.7,44.3,39.7,37.6,37.3,31.7,29.6,29.5,24.3,21.9,21.7,20.8,18.9,15.3,7.9；31P NMR(202MHz,CDCl3)δP147.6；HRMS m/z(ESI)calcd for C42H58N4O8PS+[M+H]+:809.3707,found:809.3702.
1H NMR(500MHz,CDCl3)δ7.71(d,J＝15.0Hz,1H),7.44(d,J＝3.1Hz,1H),7.27(dd,J＝14.9,3.0Hz,1H),6.96(s,1H),5.79(s,1H),5.65(s,1H),4.98(s,2H),4.11(t,J＝14.6Hz,2H),3.94-3.88(m,3H),3.66(dd,J＝24.8,13.1Hz,1H),3.49(q,J＝13.2Hz,2H),3.05(h,J＝13.0Hz,1H),2.84-2.78(m,2H),2.64-2.56(m,4H),2.30–2.01(m,7H),1.29(d,J＝13.0Hz,3H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H)；13CNMR(125MHz,CDCl3)δ173.1,169.1,158.4,158.0,153.6,145.2,143.9,143.0,136.9,132.3,132.0,123.6,119.7,118.6,118.3,117.5,103.7,96.3,77.7,73.3,73.2,68.8,63.3,59.1,58.9,50.3,45.0,44.8,41.9,41.6,31.7,29.3,28.9,26.2,23.2,22.9,21.8,17.3,14.3,7.7；31P NMR(202MHz,CDCl3)δP149.6；HRMS m/z(ESI)calcd for C39H52N4O8PS+[M+H]+:767.3238,found:767.3234.
1H NMR(500MHz,CDCl3)δ7.71(d,J＝15.0Hz,1H),7.44(d,J＝3.1Hz,1H),7.27(dd,J＝14.9,3.0Hz,1H),6.96(s,1H),5.79(s,1H),5.65(s,1H),4.99(s,2H),4.27–3.92(m,3H),3.90(t,J＝8.0,2H),3.49(q,J＝13.2Hz,2H),2.88-2.78(m,2H),2.78(dd,J＝24.8,11.5Hz,1H),2.60-2.44(m,4H),2.56–2.48(m,1H),2.36(q,J＝13.6Hz,1H),2.20–2.06(m,6H),1.22–1.14(m,6H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ172.1,169.1,158.5,158.0,153.8,145.4,143.9,136.9,132.3,132.0,123.6,119.7,118.6,118.2,116.9,103.3,96.7,76.1,70.6,70.3,67.8,63.3,59.1,58.9,50.3,44.0,43.6,40.3,40.0,31.4,29.9,29.3,25.3,22.9,22.6,21.8,21.3,21.0,14.3,7.9；31PNMR(202MHz,CDCl3)δP 147.6；HRMS m/z(ESI)calcd for C39H52N4O8PS+[M+H]+:767.3238,found:767.3230.
1H NMR(500MHz,CDCl3)δ7.70(d,J＝14.8Hz,1H),7.43(d,J＝2.9Hz,1H),7.26(dd,J＝15.0,2.9Hz,1H),6.99(s,1H),5.79(s,1H),5.67(s,1H),4.94(s,2H),4.10(t,J＝14.9Hz,2H),3.90(t,J＝8.0,2H),3.48(q,J＝13.2Hz,2H),3.33(t,J＝9.0Hz,2H),3.15(s,1H),2.89-2.77(m,2H),2.61-2.54m,4H),2.50(td,J＝15.9,1.3Hz,2H),2.30–2.06(m,3H),1.99(q,J＝13.6Hz,1H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.98(s,9H),0.89(t,J＝13.6Hz,3H),0.21(s,6H)；13C NMR(125MHz,CDCl3)δ172.8,158.4,158.0,153.6,150.0,145.2,143.9,136.9,132.0,131.8,123.6,120.0,118.6,118.4,117.53,103.7,95.3,78.9,68.8,63.5,63.4,63.3,59.1,58.8,50.3,44.6,44.4,32.8,32.5,31.4,29.8,29.0,26.2,25.6,22.9,22.7,20.4,13.3,7.9,-0.7；31P NMR(202MHz,CDCl3)δP 148.6；HRMSm/z(ESI)calcd for C42H62N4O7PSSi+[M+H]+:825.3841,found:825.3840.
1H NMR(500MHz,CDCl3)δ7.70(d,J＝14.8Hz,1H),7.63-7.55(m,4H),7.43(d,J＝2.9Hz,1H),7.40-7.32(m,6H),7.26(dd,J＝15.0,2.9Hz,1H),6.99(s,1H),5.79(s,1H),5.67(s,1H),4.94(s,2H),4.10(t,J＝14.9Hz,2H),3.90(t,J＝8.0,2H),3.48(q,J＝13.2Hz,2H),3.33(t,J＝9.0Hz,2H),3.15(s,1H),2.86-2.79(m,2H),2.62-2.56(m,4H),2.50(td,J＝15.9,1.3Hz,2H),2.30–2.06(m,3H),1.99(q,J＝13.6Hz,1H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.98(s,9H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ172.8,158.6,158.4,153.8,149.9,145.2,143.9,136.9,135.1,132.4,132.3,131.7,130.2,129.3,123.6,119.7,118.6,118.4,116.9,104.7,96.7,80.4,67.8,63.4,63.2,63.0,59.1,58.7,51.3,44.9,44.6,32.8,32.3,31.4,29.8,29.0,27.7,26.0,22.9,22.5,20.0,14.3,7.9；31P NMR(202MHz,CDCl3)δP149.6；HRMS m/z(ESI)calcd forC52H66N4O7PSSi+[M+H]+:949.4154,found:949.4150.
1H NMR(500MHz,CDCl3)δ7.70(d,J＝14.8Hz,1H),7.43(d,J＝2.9Hz,1H),7.26(dd,J＝15.0,2.9Hz,1H),6.99(s,1H),5.79(s,1H),5.67(s,1H),5.45(s,2H),4.94(s,2H),4.10(t,J＝14.9Hz,2H),3.90(t,J＝8.0,2H),3.48(q,J＝13.2Hz,2H),3.33(t,J＝9.0Hz,2H),3.28(s,3H),3.15(s,1H),2.84-2.77(m,2H),2.62-2.54(m,4H),2.50(td,J＝15.9,1.3Hz,2H),2.30–2.06(m,3H),1.99(q,J＝13.6Hz,1H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ172.9,158.4,158.1,153.7,145.2,143.9,143.1,136.9,132.3,132.0,123.6,119.7,118.6,118.2,,103.3,94.7,92.7,77.4,68.8,63.4,63.3,63.2,59.1,58.9,55.5,50.3,44.6,44.3,32.8,32.6,31.2,29.8,28.6,26.2,22.9,22.7,14.3,7.9；31P NMR(202MHz,CDCl3)δP 149.6；HRMS m/z(ESI)calcd forC38H52N4O8PS+[M+H]+:755.3238,found:755.3236.
1H NMR(500MHz,CDCl3)δ7.70(d,J＝14.8Hz,1H),7.43(d,J＝2.9Hz,1H),7.26(dd,J＝15.0,2.9Hz,1H),6.99(s,1H),5.79(s,1H),5.67(s,1H),4.94(s,2H),4.10(t,J＝14.9Hz,2H),3.90(t,J＝8.0,2H),3.48(q,J＝13.2Hz,2H),3.33(t,J＝9.0Hz,2H),3.15(s,1H),2.84-2.77(m,2H),2.62-2.54(m,4H),2.50(td,J＝15.9,1.3Hz,2H),2.30–2.06(m,3H),1.99(q,J＝13.6Hz,1H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H),0.21(s,9H)；13C NMR(125MHz,CDCl3)δ172.8,158.4,158.3,153.6,150.0,145.2,143.9,136.9,132.1,132.0,123.6,119.7,118.6,118.5,117.5,103.7,95.3,77.6,68.8,63.5,63.3,63.2,59.1,59.0,50.3,44.6,44.5,32.8,32.7,31.4,29.8,29.0,26.2,22.9,22.8,14.3,7.9,2.4；31P NMR(202MHz,CDCl3)δP 147.6；HRMS m/z(ESI)calcd forC39H56N4O7PSSi+[M+H]+:783.3371,found:783.3370.
1H NMR(500MHz,CDCl3)δ7.93(d,J＝3.1Hz,1H),7.70(d,J＝14.9Hz,1H),7.28(dd,J＝14.9,3.0Hz,1H),7.14(t,J＝3.0Hz,1H),6.92(s,1H),5.82(s,2H),4.96(s,2H),4.11(t,J＝14.9Hz,2H),3.90(t,J＝8.0,2H),3.33(t,J＝9.2Hz,2H),2.84-2.77(m,2H),2.62-2.50(m,6H),2.28–1.97(m,7H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ173.1,169.0,160.8,158.3,151.5,143.0,142.8,137.5,135.2,130.3,128.8,126.8,120.0,118.5,118.4,117.5,107.3,96.4,77.7,68.8,63.5,65.3,65.2,59.0,49.8,50.7,44.5,44.3,32.8,32.5,31.4,29.8,29.2,22.9,22.7,21.7,7.9；31P NMR(202MHz,CDCl3)δP 148.4；HRMS m/z(ESI)calcd for C36H46N4O8PS+[M+H]+:725.2768,found:725.2765.
1H NMR(500MHz,CDCl3)δ8.04(s,1H),7.57(d,J＝15.0Hz,1H),7.25(d,J＝15.0Hz,1H),6.96(s,1H),5.82(s,2H),4.98(s,2H),4.39(s,2H),4.11(t,J＝15.0Hz,2H),3.90(t,J＝8.0,2H),3.33(t,J＝14.6Hz,2H),2.85-2.75(m,8H),2.64–2.47(m,6H),2.26–2.01(m,7H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ173.1,169.1,162.1,158.3,147.6,147.4,143.1,137.6,134.9,128.3,124.0,123.6,120.9,118.6,118.4,117.5,114.9,96.5,77.7,69.2,63.5,63.3,62.1,59.1,59.0,55.7,50.7,44.6,44.3,44.0,32.8,32.5,31.4,29.8,29.3,22.9,22.7,21.8,7.9；31P NMR(202MHz,CDCl3)δP148.6；HRMS m/z(ESI)calcd for C39H53N5O8PS+[M+H]+:782.3347,found:782.3345.
1H NMR(500MHz,CDCl3)δH8.94,(s,1H),7.95(d,J＝15.0Hz,1H),7.40(d,J＝2.9Hz,1H),6.93(s,1H),5.77(s,1H),5.62(s,1H),4.95(s,2H),4.09(t,J＝14.9Hz,2H),3.90(t,J＝8.0,2H),3.47(q,J＝13.2Hz,2H),3.31(t,J＝14.9Hz,2H),2.97-2.85(m,2H),2.70(t,J＝6.5Hz,2H),2.59–2.46(m,4H),2.26–2.00(m,7H),1.20(dd,J＝6.8,2.3Hz,12H),1.17(t,J＝13.2Hz,3H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ173.1,169.1,158.3,153.9,146.5,145.9,143.1,137.6,132.8,130.3,129.5,128.1,125.0,118.6,118.5,117.5,96.5,77.7,69.2,63.5,63.4,63.3,59.1,59.0,50.7,44.6,44.3,32.8,32.6,31.4,29.8,29.3,23.9,23.7,21.8,7.9；31P NMR(202MHz,CDCl3)δP 145.6；HRMSm/z(ESI)calcd for C36H45N5O10PS+[M+H]+:770.2619,found:770.2617.
1H NMR(500MHz,CDCl3)δ8.08(s,1H),7.59(d,J＝15.0Hz,1H),7.25(d,J＝15.0Hz,1H),6.93(s,1H),5.80(d,J＝7.5Hz,2H),4.95(s,2H),4.78(s,2H),4.09(t,J＝14.9Hz,2H),3.90(t,J＝8.0,2H),3.56(q,J＝11.7Hz,2H),3.31(t,J＝9.1Hz,2H),2.92-2.83(m,2H),2.62-2.54(m,6H),2.25–2.00(m,7H),1.17(t,J＝11.8Hz,3H),1.20(dd,J＝6.8,2.3Hz,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ173.1,169.1,160.9,158.3,148.8,145.6,143.1,137.6,132.0,129.5,127.5,123.1,118.8,118.6,118.1,117.5,116.9,96.5,77.7,69.2,68.7,66.7,63.3,63.2,63.1,59.0,58.9,50.7,44.7,44.3,32.8,32.6,31.4,29.8,29.3,22.9,22.6,21.6,14.9,7.6；31P NMR(202MHz,CDCl3)δP 148.6；HRMSm/z(ESI)calcd for C39H52N4O9PS+[M+H]+:783.3187,found:783.3184.
1H NMR(500MHz,CDCl3)δ7.93(d,J＝3.1Hz,1H),7.70(d,J＝14.9Hz,1H),7.28(dd,J＝14.9,3.0Hz,1H),7.14(t,J＝3.0Hz,1H),6.92(s,1H),5.82(s,2H),4.96(s,2H),4.11(t,J＝14.9Hz,2H),3.90(t,J＝8.0,2H),3.33(t,J＝9.2Hz,2H),2.84-2.77(m,2H),2.62-2.50(m,6H),2.28–1.97(m,7H),1.06(d,J＝6.8,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ173.1,169.1,158.3,149.8,149.1,143.1,141.4,137.6,135.5,133.5,129.4,128.0,118.7,118.5,118.4,117.5,106.5,96.5,77.7,63.3,63.2,62.9,59.1,59.0,50.7,44.6,44.3,43.5,33.2,32.8,32.6,29.3,29.1,22.9,22.7,21.8,8.0；31P NMR(202MHz,CDCl3)δP 147.8；HRMS m/z(ESI)calcd for C36H47N5O7PS+[M+H]+:724.2928,found:724.2926.
1H NMR(500MHz,CD3CN)δH7.98(d,J＝10.0Hz,1H),7.61-7.54(m,2H),7.50-7.44(m,2H),7.40-7.30(m,6H),7.25-7.19(m,1H),7.08(s,1H),6.75(t,J＝8.1Hz,4H),5.52(d,J＝16.7Hz,1H),5.33(d,J＝16.7Hz,1H),5.25(d,J＝2.6Hz,2H),4.21(q,J＝6.2Hz,2H),4.07-3.95(m,2H),3.91-3.78(m,1H),3.67-3.60(m,6H),3.52-3.48(m,3H),3.26-3.21(m,1H),3.17-3.10(m,2H),3.05-2.94(m,1H),2.90-2.85(m,3H),2.80-2.72(m,1H),2.56(t,J＝6.0Hz,1H),2.15-2.01(m,4H),1.34(t,J＝7.6Hz,3H),1.26-1.13(m,9H),1.00(d,J＝6.8Hz,3H),0.90(t,J＝7.4Hz,3H)；13C NMR(125MHz,CD3CN)δ172.0,168.3,158.1,157.9,157.6,155.6,149.2,145.1,144.5,144.1,137.8,136.7,134.0,132.6,130.5,129.3,128.1,129.0,125.1,120.2,120.0,119.8,118.8,114.3,105.1,96.3,89.4,78.1,75.5,75.0,69.8,66.7,65.0,64.1,60.0,59.7,57.3,52.4,47.1,45.2,37.1,36.2,33.0,30.1,29.8,27.3,24.0,23.6,15.3,8.1；31P NMR(202MHz,CD3CN)δP 148.6,148.5；HRMS m/z(ESI)calcd for C58H67N4O10PS+[M+H]+:1042.4316,found:1042.4311.
1H NMR(500MHz,CD3CN)δH8.01(d,J＝10.0Hz,1H),7.51-7.45(m,2H),7.44-7.38(m,2H),7.37-7.26(m,6H),7.25-7.19(m,1H),7.02(s,1H),6.85(t,J＝8.1Hz,4H),5.57(d,J＝16.7Hz,1H),5.38(d,J＝16.7Hz,1H),5.15(d,J＝2.6Hz,2H),4.26(q,J＝6.2Hz,2H),4.17-4.05(m,2H),3.92-3.78(m,1H),3.77-3.73(m,6H),3.72-3.49(m,3H),3.28-3.24(m,1H),3.18-3.12(m,2H),3.06-2.96(m,1H),2.94-2.82(m,3H),2.81-2.72(m,1H),2.52(t,J＝6.0Hz,1H),2.21(d,J＝1.1Hz,3H),2.17-2.05(m,4H),1.33(t,J＝7.6Hz,3H),1.23-1.14(m,9H),1.07(d,J＝6.8Hz,3H),1.00(t,J＝7.4Hz,3H)；13C NMR(125MHz,CD3CN)δ173.0,169.1,158.7,158.4,158.3,153.6,145.2,144.1,143.9,143.1,136.9,135.5,132.0,131.8,129.4,128.4,128.2,128.1,123.6,119.7,118.6,118.5,117.5,113.5,103.7,95.3,87.4,77.7,74.5,74.3,68.8,64.7,64.3,63.3,59.1,59.0,56.1,50.3,44.6,44.3,35.3,35.0,31.4,29.9,29.3,26.2,22.9,22.6,21.8,14.3,7.5；31P NMR(202MHz,CD3CN)δP148.6,148.2；HRMS m/z(ESI)calcd for C60H70N4O11PS+[M+H]+:1085.4494,found:1085.4490.
1H NMR(500MHz,CD3CN)δ7.71(d,J＝15.0Hz,1H),7.44(d,J＝2.9Hz,1H),7.37–7.34(m,2H),7.34–7.31(m,2H),7.30–7.23(m,6H),6.96(s,1H),6.92–6.89(m,2H),6.89–6.86(m,2H),5.77(s,1H),5.66(s,1H),4.97(s,2H),4.53–4.36(m,1H),3.97-3.88(m,4H),3.79(s,6H),3.70(dd,J＝24.8,11.3Hz,1H),3.44(m,3H),3.16(m,1H),2.89-2.75(m,3H),2.62-2.55(m,3H),2.25–2.19(m,1H),2.12–2.01(m,6H),1.29(d,J＝12.6Hz,3H),1.23-1.14(m,9H),1.18(t,J＝13.2Hz,3H),1.07(d,J＝6.8Hz,3H),0.89(t,J＝13.6Hz,3H)；13CNMR(125MHz,CD3CN)δ173.0,169.1,158.7,158.4,158.3,153.6,145.2,144.1,143.9,143.1,136.9,135.5,132.0,131.8,129.4,128.4,128.2,128.1,123.6,119.7,118.6,118.5,117.5,113.5,103.7,95.3,87.4,77.7,74.5,74.3,68.8,64.7,64.3,63.3,59.1,59.0,56.1,50.3,44.6,44.3,35.3,35.0,31.4,29.9,29.3,26.2,22.9,22.6,21.8,14.3,7.5；31P NMR(202MHz,CD3CN)δP 149.6,149.2；HRMS m/z(ESI)calcd for C61H72N4O11PS+[M+H]+:1099.4650,found:1099.4654.
1H NMR(500MHz,CD3Cl)δ7.71(d,J＝15.0Hz,1H),7.44(d,J＝3.1Hz,1H),7.38–7.34(m,2H),7.35–7.32(m,2H),7.30–7.21(m,11H),6.96(s,1H),6.93–6.86(m,4H),5.77(s,1H),5.66(s,1H),4.98(s,2H),4.75(t,J＝6.8Hz,1H),4.28(tt,J＝13.9,2.9Hz,1H),3.95-3.88(m,4H),3.79(s,6H),3.72(dd,J＝24.8,3.0Hz,1H),3.54–3.37(m,3H),2.83-2.78(m,3H),2.60–2.35(m,5H),2.21(q,J＝13.6Hz,1H),2.13–2.00(m,4H),1.23-1.14(m,9H),1.18(t,J＝13.2Hz,3H),1.07(d,J＝6.8Hz,3H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ172.1,169.1,158.8,158.2,157.8,156.2,145.3,144.0,143.8,143.6,141.9,135.2,132.8,132.3,131.9,129.3,129.0,128.2,128.1,127.9,127.7,126.1,123.1,119.6,118.6,118.4,113.4,113.2,103.7,97.6,87.8,80.1,74.7,74.5,68.3,64.7,64.5,62.3,59.1,56.0,51.3,49.9,44.5,44.3,34.7,34.2,34.1,29.6,27.3,22.9,22.7,21.7,14.3,7.9；31P NMR(202MHz,CDCl3)δP 148.6,148.4；HRMS m/z(ESI)calcd forC66H74N4O11PS+[M+H]+:1161.4807,found:1161.4802.
1H NMR(500MHz,CDCl3)δ7.71(d,J＝15.0Hz,1H),7.44(d,J＝3.1Hz,1H),7.38–7.35(m,2H),7.34–7.31(m,2H),7.30–7.24(m,6H),6.99(s,1H),6.92–6.84(m,4H),5.80(s,1H),5.69(s,1H),4.98(s,2H),4.26(tt,J＝14.8,3.1Hz,1H),3.99-3,91(m,4H),3.79(s,6H),3.65(dd,J＝24.8,3.0Hz,1H),3.47(ddd,J＝24.7,22.0,8.1Hz,3H),2.86-2.78(m,3H),2.62-2.54(m,3H),2.30–2.01(m,8H),1.23-1.14(m,9H),1.18(t,J＝13.2Hz,3H),1.07(d,J＝6.8Hz,3H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ172.1,169.1,158.9,158.4,158.2,153.6,145.2,144.1,143.9,143.1,136.9,135.5,132.0,129.8,129.4,128.4,128.2,128.1,123.6,119.7,118.6,118.4,117.5,113.5,103.7,95.3,87.4,77.7,75.0,74.8,70.8,64.7,64.5,63.3,59.0,58.8,56.1,50.3,44.6,44.3,43.3,42.2,32.9,32.7,29.9,29.3,26.2,22.9,22.7,21.8,14.3,7.9；31P NMR(202MHz,CDCl3)δP 148.3,148.0；HRMS m/z(ESI)calcd for C62H74N4O11PS+[M+H]+:1113.4807,found:1113.4802.
1H NMR(500MHz,CDCl3)δ7.71(d,J＝15.0Hz,1H),7.44(d,J＝3.1Hz,1H),7.38–7.34(m,2H),7.34–7.30(m,2H),7.30–7.24(m,6H),6.98(s,1H),6.92–6.89(m,2H),6.90–6.85(m,2H),5.80(s,1H),5.69(s,1H),4.98(s,2H),4.40(tt,J＝14.4,12.3Hz,1H),4.03(dd,J＝24.8,13.2Hz,1H),3.91–3.65(m,10H),3.47-3.35(m,3H),2.85-2.78(m,3H),2.65–2.49(m,4H),2.39–1.98(m,7H),1.18(t,J＝13.2Hz,3H),1.06(d,J＝6.8,12H),0.95(d,J＝12.8Hz,3H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ171.1,168.1,158.8,158.4,157.5,153.6,145.2,144.1,143.9,143.1,136.7,135.5,132.0,129.9,129.4,128.4,128.3,128.0,123.5,119.6,118.5,118.4,117.4,113.3,104.7,95.3,87.4,77.5,74.5,74.3,73.8,64.7,64.5,63.3,59.1,58.9,56.1,50.3,44.6,44.5,38.6,35.0,34.9,32.6,29.3,26.2,22.9,22.8,21.8,16.7,14.3,7.9；31P NMR(202MHz,CDCl3)δP 147.5,147.2；HRMS m/z(ESI)calcd for C61H72N4O11PS+[M+H]+:1099.4650,found:1099.4658.
1H NMR(500MHz,CDCl3)δ7.71(d,J＝14.8Hz,1H),7.44(d,J＝2.9Hz,1H),7.37–7.34(m,2H),7.33–7.30(m,2H),7.29–7.23(m,6H),7.13(s,1H),6.92–6.89(m,2H),6.89–6.85(m,2H),5.68(d,J＝20.5Hz,2H),4.96(s,2H),4.38-4.35(m,1H),4.11(t,J＝10.0Hz,2H),3.90(t,J＝8.0,2H),3.79(s,6H),3.64(dd,J＝24.8,3.4Hz,1H),3.49(q,J＝13.4Hz,2H),3.32(dd,J＝24.8,3.4Hz,1H),2.85-2.78(m,3H),2.65–2.42(m,6H),2.23–2.10(m,3H),2.03(q,J＝13.6Hz,1H),1.18(t,J＝13.4Hz,3H),1.06(d,J＝6.8,12H),0.98(s,9H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ172.8,159.0,158.4,158.3,153.6,149.9,145.2,144.1,143.9,136.9,135.5,132.0,129.9,129.4,128.4,128.1,128.0,123.6,119.7,118.6,118.3,117.5,113.5,103.7,95.3,87.4,78.9,74.5,74.3,68.8,64.7,64.3,63.3,59.0,58.9,56.1,50.2,44.5,44.0,35.6,35.1,31.4,29.9,29.1,26.2,25.6,22,5,21.9,20.4,14.3,7.8,-0.7；31P NMR(202MHz,CDCl3)δP147.4,147.2；HRMS m/z(ESI)calcd for C64H82N4O10PSSi+[M+H]+:1157.5253,found:1157.5251.
1H NMR(500MHz,CDCl3)δ7.71(d,J＝7.5Hz,1H),7.62–7.56(m,4H),7.44(d,J＝1.6Hz,1H),7.39–7.32(m,10H),7.30–7.23(m,6H),7.12(s,1H),6.89(d,J＝7.5Hz,4H),5.79(s,1H),5.59(s,1H),4.69(d,J＝1.4Hz,2H),4.32-4.29(m,1H),4.11(t,J＝7.4Hz,2H),3.90(t,J＝8.0,2H),3.79(s,6H),3.68(dd,J＝12.5,7.1Hz,1H),3.49(q,J＝6.6Hz,2H),3.43(dd,J＝12.3,7.1Hz,1H),2.86-2.78(m,3H),2.64-2.57(m,5H),2.53(dd,J＝12.3,5.1Hz,1H),2.25–2.17(m,3H),2.10(t,J＝6.8Hz,1H),1.18(t,J＝5.9Hz,3H),1.06(d,J＝6.8,12H),0.98(s,9H),0.89(t,J＝6.8Hz,3H)；13C NMR(125MHz,CDCl3)δ172.7,158.9,158.4,158.3,153.6,149.9,145.2,144.1,143.9,136.8,135.4,1351,132.0,131.9,131.6,130.1,129.3,129.0,128.4,128.1,123.6,119.6,118.6,117.5,113.5,103.7,95.2,87.4,80.3,74.7,74.5,68.8,64.8,64.7,63.3,59.1,59.0,56.1,50.3,44.5,44.2,35.3,35.0,31.4,29.9,29.0,26.7,26.1,22.9,22.8,20.0,14.3,7.8；31P NMR(202MHz,CDCl3)δP147.4,147.2；HRMS m/z(ESI)calcd for C74H86N4O10PSSi+[M+H]+:1281.5566,found:1281.5560.
1H NMR(500MHz,CDCl3)δ7.68(d,J＝15.0Hz,1H),7.41(d,J＝3.0Hz,1H),7.34–7.31(m,2H),7.31–7.27(m,2H),7.27–7.20(m,6H),6.96(s,1H),6.90–6.86(m,2H),6.86–6.83(m,2H),5.78(s,1H),5.65(s,1H),5.33(s,2H),4.93(s,2H),4.11–3.98(m,3H),3.96–3.82(m,3H),3.77(s,6H),3.48(q,J＝13.1Hz,2H),3.36–3.26(m,1H),2.89–2.72(m,5H),2.66–2.46(m,3H),2.25–2.04(m,3H),1.98(q,J＝13.6Hz,1H),1.17(t,J＝13.2Hz,3H),1.06(d,J＝12.1Hz,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ172.9,158.9,158.3,158.1,153.6,145.2,144.1,143.9,143.0,136.8,135.4,132.0,129.9,129.3,128.3,128.1,128.0,123.5,122.7,119.6,118.5,118.3,113.5,103.7,95.2,92.7,87.4,77.4,74.5,74.7,68.8,64.7,64.6,63.2,59.0,58.8,56.0,55.5,50.2,44.5,44.1,35.3,35.0,31.4,29.9,28.5,26.1,22.9,22.7,14.3,7.8；31P NMR(202MHz,CDCl3)δP 148.6,148.3；HRMS m/z(ESI)calcd for C60H72N4O11PS+[M+H]+:1087.4650,found:1087.4655.
1H NMR(500MHz,CDCl3)δ7.70(d,J＝15.0Hz,1H),7.43(d,J＝2.9Hz,1H),7.37–7.33(m,2H),7.33–7.30(m,2H),7.30–7.24(m,6H),7.01(s,1H),6.94–6.89(m,2H),6.88–6.84(m,2H),5.69(s,1H),5.56(s,1H),4.94(s,2H),4.45-4.41(m,1H),4.11(t,J＝9.4Hz,2H),3.90(t,J＝8.0,2H),3.79(s,6H),3.70(dd,J＝24.8,10.9Hz,1H),3.56–3.38(m,3H),2.88-2.78(m,3H),2.69–2.44(m,5H),2.18–1.94(m,4H),1.18(t,J＝13.4Hz,3H),1.06(d,J＝6.0Hz,12H),0.89(t,J＝13.6Hz,3H),0.21(s,9H)；13C NMR(125MHz,CDCl3)δ172.8,159.0,158.4,158.3,153.6,150.0,145.2,144.1,143.9,136.9,135.5,132.0,131.9,129.4,128.4,128.3,128.0,123.6,119.7,118.6,118.4,113.5,103.7,95.3,87.4,77.6,74.5,74.4,68.8,64.7,64.6,63.3,59.1,58.9,56.0,50.2,44.5,44.3,35.3,35.2,31.4,29.9,29.0,26.2,22.9,22.8,14.3,8.2,2.4；31P NMR(202MHz,CDCl3)δP 149.4,149.2；HRMSm/z(ESI)calcd for C61H76N4O10PSSi+[M+H]+:1115.4784,found:1115.4780.
1H NMR(500MHz,CDCl3)δ7.94(d,J＝3.1Hz,1H),7.71(d,J＝15.0Hz,1H),7.37–7.34(m,2H),7.34–7.30(m,3H),7.29–7.25(m,5H),7.15(t,J＝3.0Hz,1H),6.93(s,1H),6.92–6.89(m,2H),6.89–6.86(m,2H),5.84(d,J＝5.1Hz,2H),4.97(s,2H),4.11(t,J＝15.0Hz,2H),3.93–3.63(m,9H),3.35(dd,J＝24.7,11.0Hz,1H),2.86-2.78(m,3H),2.73–2.45(m,5H),2.33–1.93(m,8H),1.06(d,J＝6.0Hz,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ173.1,169.1,160.9,159.0,158.3,151.0,144.1,143.1,142.8,137.6,135.5,135.2,130.3,129.4,128.9,128.3,128.1,128.0,120.1,118.6,118.5,117.6,113.5,107.3,96.5,87.4,77.7,74.5,74.4,68.8,64.7,64.5,63.3,59.1,59.0,56.1,50.7,44.5,44.4,35.3,35.2,31.4,29.9,29.3,22.9,22.8,21.8,8.2；31P NMR(202MHz,CDCl3)δP146.4,146.2；HRMS m/z(ESI)calcd for C58H66N4O11PS+[M+H]+:1057.4181,found:1057.4181.
1H NMR(500MHz,CDCl3)δ8.63(s,1H),7.95(d,J＝15.0Hz,1H),7.40(d,J＝15.0Hz,1H),7.37–7.34(m,2H),7.33–7.30(m,2H),7.29–7.24(m,5H),6.92(s,1H),6.92–6.89(m,2H),6.89–6.86(m,2H),5.84(s,2H),4.97(s,2H),4.25(tt,J＝13.9,3.4Hz,1H),4.11(t,J＝15.0Hz,2H),3.90(t,J＝8.0,2H),3.79(s,6H),3.68(dd,J＝24.7,3.5Hz,1H),3.45(dd,J＝24.8,3.4Hz,1H),2.86-2.78(m,3H),2.73–2.46(m,5H),2.24–1.96(m,7H),1.06(d,J＝6.0Hz,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ173.1,169.1,160.9,159.0,158.3,153.9,146.5,144.1,143.1,137.6,135.5,132.8,130.3,129.4,129.3,128.3,128.2,128.0,125.0,118.6,118.5,117.5,113.5,96.5,87.4,77.7,74.5,74.4,69.2,64.7,64.5,63.3,59.1,59.0,56.1,50.7,44.5,44.4,35.3,35.2,31.4,29.9,29.3,22.9,22.7,21.8,7.9；31P NMR(202MHz,CDCl3)δP 149.0,148.8；HRMS m/z(ESI)calcd for C58H65N5O13PS+[M+H]+:1102.4032,found:1102.4039.
1H NMR(500MHz,CDCl3)δ8.04(s,1H),7.57(d,J＝15.0Hz,1H),7.37–7.34(m,2H),7.34–7.31(m,2H),7.29–7.25(m,5H),6.96(s,1H),6.92–6.89(m,2H),6.88–6.86(m,2H),5.82(d,J＝11.5Hz,2H),4.98(s,2H),4.47-4.40(m,1H),4.39(s,2H),4.11(t,J＝14.7Hz,2H),3.90(t,J＝8.0,2H),3.79(s,6H),3.67(dd,J＝24.7,13.2Hz,1H),3.36(dd,J＝24.7,13.2Hz,1H),2.85–2.69(m,9H),2.64–2.45(m,5H),2.29–2.14(m,3H),2.12–2.00(m,4H),1.06(d,J＝6.0Hz,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ173.1,169.1,162.1,158.9,158.3,147.6,147.5,144.1,143.1,137.6,135.5,134.8,129.4,128.6,128.5,128.3,128.0,127.9,124.0,123.6,118.6,118.5,117.5,114.5,113.5,96.5,87.4,77.7,74.5,74.4,69.2,64.7,64.5,63.3,59.1,59.0,55.7,50.7,44.6,44.4,44.0,35.3,35.2,31.4,29.9,29.3,22.9,22.7,21.8,7.9；31P NMR(202MHz,CDCl3)δP 148.0,147.8；HRMS m/z(ESI)calcd for C61H73N5O11PS+[M+H]+:1114.4759,found:1114.4756.
1H NMR(500MHz,CDCl3)δ8.12(s,1H),7.62(d,J＝15.0Hz,1H),7.37–7.34(m,2H),7.33(d,J＝2.3Hz,2H),7.29–7.24(m,5H),6.96(s,1H),6.92–6.89(m,2H),6.87(d,J＝3.4Hz,2H),5.85(s,2H),5.00(s,2H),4.80(s,2H),4.56–4.36(m,1H),4.11(t,J＝15.0Hz,2H),3.90(t,J＝8.0,2H),3.82–3.68(m,7H),3.58(q,J＝11.9Hz,2H),3.39(dd,J＝24.8,10.7Hz,1H),2.85-2.78(m,3H),2.65–2.47(m,5H),2.38(q,J＝13.6Hz,1H),2.20–2.09(m,6H),1.18(t,J＝11.8Hz,3H),1.06(d,J＝6.0Hz,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ173.1,169.1,160.9,158.9,158.3,148.8,145.5,144.1,143.1,137.6,135.5,131.8,129.4,129.3,128.6,128.5,128.0,127.4,123.0,118.6,118.5,118.1,117.5,116.9,113.5,96.5,87.4,77.7,74.5,74.4,69.2,68.7,66.7,64.7,64.5,63.3,59.1,59.0,56.1,50.7,44.6,44.4,44.0,35.3,35.2,31.4,29.9,29.3,22.9,22.7,21.8,14.8,7.9；31P NMR(202MHz,CDCl3)δP 148.5,148.0；HRMS m/z(ESI)calcd for C61H72N4O12PS+[M+H]+:1115.4600,found:1115.4603.
1H NMR(500MHz,CDCl3)δ8.40(dd,J＝14.9,3.0Hz,1H),7.84(d,J＝2.9Hz,1H),7.34(q,J＝3.2Hz,2H),7.33–7.30(m,2H),7.27–7.24(m,5H),6.93(s,1H),6.91–6.88(m,2H),6.88–6.85(m,2H),6.71(t,J＝2.9Hz,1H),5.82(d,J＝6.0Hz,2H),4.98(s,2H),4.48-4.443(m,1H),4.08(s,1H),3.90(t,J＝8.0,2H),3.85–3.66(m,7H),3.46–3.21(m,3H),2.84-2.78(m,3H),2.66–2.48(m,5H),2.39(q,J＝13.5Hz,1H),2.15(q,J＝13.6Hz,1H),2.09(s,3H),2.01–1.81(m,2H),1.06(d,J＝6.0Hz,12H),0.89(t,J＝13.6Hz,3H)；13C NMR(125MHz,CDCl3)δ173.1,169.1,159.0,158.3,149.8,149.1,144.1,143.1,141.4,137.6,135.5,135.4,133.5,129.4,129.3,128.4,128.3,128.0,127.9,118.7,118.6,118.4,117.5,113.5,106.5,96.5,87.4,77.7,74.5,74.4,64.7,64.5,63.3,59.1,59.0,56.1,50.7,44.6,44.4,43.4,35.3,35.2,33.1,29.3,29.2,22.9,22.7,21.8,7.9；31P NMR(202MHz,CDCl3)δP 148.7,148.4；HRMS m/z(ESI)calcd for C58H67N5O10PS+[M+H]+:1056.4341,found:1056.4340.
实施例3.核酸适体修饰
在本实施例中，利用实施例2中任意一种喜树碱衍生物，对核酸适体，尤其是核酸适体sgc8进行修饰。以实施例2中任意一种喜树碱衍生物作为固相合成模块，通过固相合成仪自动引入到核酸适体sgc8中。
本发明已由上述相关实施例加以描述，然而上述实施例仅为实施本发明的范例。必需指出的是，已公开的实施例并未限制本发明的范围。相反地，包含于权利要求书的精神及范围的修改及均等设置均包括于本发明的范围内。
Claims (10)
1.一种喜树碱衍生物，具有式I所示的结构：
R1为H、取代或未取代的具有1-4个碳原子的直链或支链烷基、-C(O)Ra1、-CNRb1Rc1或-NO2；
R2为H、取代或未取代的具有1-4个碳原子的直链或支链烷基、-C(O)Ra1、-CNRb1Rc1或-NO2；
R3为H或羟基保护基；
X为O或N；
L为取代或未取代的具有1-20个碳原子的直链或支链杂烷基；
W为H或-COWa1；
Ra1、Rb1、Rc1独立地为具有1-4个碳原子的直链或支链烷基；
Wa1为保护基团。
2.如权利要求1所述的喜树碱衍生物，具有式I-a所示的结构：
L1为取代或未取代的具有1-6个碳原子的直链或支链烷基；
L2为取代或未取代的具有1-14个碳原子的直链或支链杂烷基。
3.如权利要求1所述的喜树碱衍生物，具有式I-a-1或式I-a-2所示的结构：
L1为取代或未取代的具有1-6个碳原子的直链或支链烷基；
L2为取代或未取代的具有1-14个碳原子的直链或支链杂烷烃。
4.如权利要求1所述的喜树碱衍生物，其特征在于，所述具有1-20个碳原子的直链或支链杂烷基的杂原子为O或S。
5.如权利要求1所述的喜树碱衍生物，其特征在于，所述保护基团为DMTr。
6.如权利要求1所述的喜树碱衍生物，其特征在于，所述羟基保护基为-Ac，-TBS，-TBDPS，-MOM，或-TMS。
7.如权利要求1所述的喜树碱衍生物，其特征在于，当R1、R2或L被取代时，取代基独立地选自具有1-4个碳原子的烷基或苯基。
8.如权利要求1所述的喜树碱衍生物的制备方法，其特征在于，所述制备方法是以羟基喜树碱与烯基溴化合物反应完全后，加入羟基保护试剂并以4-二甲氨基吡啶为催化剂反应至完全，以获得中间产物1；在保护气体下，以偶氮二异丁腈为引发剂，使中间产物1与硫醇类化合物或硫代甘油反应至完全以获得中间产物2或中间产物3；以4-二甲氨基吡啶为催化剂，使中间产物3与DMTrCl室温反应至完全以获得中间产物4；在N,N-二异丙基乙胺的催化下，分别使中间产物2或4与2-氰乙基-N,N-二异丙基氯代亚磷酰胺室温反应完全，以获得目标产物1或2；其中，
目标产物1具有式I-a-1所示的结构，目标产物2具有式I-a-2所示的结构：
L1为取代或未取代的具有1-6个碳原子的直链或支链烷基；
L2为取代或未取代的具有1-14个碳原子的直链或支链杂烷基。
9.如权利要求8所述的制备方法，其特征在于，所述羟基保护试剂为乙酸酐、MOMCl、TBSCl、TBDPSCl或TMSCl。
10.如权利要求1所述的喜树碱衍生物在核酸适体修饰中的应用。
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